The present invention relates to novel aza ligands able to complex metal ions, in particular paramagnetic ions, and the use of the corresponding complexes as contrast agents for magnetic resonance imaging (MRI).
A number of complexes of paramagnetic metal ions with cyclic and acyclic aza ligands are known as contrast agents in the MRI diagnostic technique (see for instance: The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging, Merbach A. E. and Toth E. Eds., John Wiley and sons, Chichester, 2001; Caravan P. et al. Chem. Rev. 1999, 99, 2293-2352 and U.S. Pat. Nos. 4,885,363; 4,916,246; 5,132,409; 6,149,890). Some of these complexes (Gd-DTPA, Gd-DOTA, Gd-HPDO3A, and the like) have recently been marketed.
The paramagnetic metal ions most extensively used in MRI diagnostics are either in the transitions metals and in the Lanthanide series. As far as Lanthanides are concerned, the attention is essentially focused on Gd(III) ion both for its high paramagnets (7 unpaired electrons) and for its favorable properties in terms of electronic relaxation. This metal does not possess any physiological function in mammalians, and its administration as free ion is strongly toxic even at low doses (10-20 micromol/Kg). For this reason, it is necessary to use ligands that form chelates with the lanthanide ion endowed with high thermodynamic and kinetic stability. This means that the chelating ligand should exhibit a high level of affinity and selectivity for the relevant paramagnetic ions as opposed to the physiological ions. Moreover, the ligand should show suitable pharmacokinetic properties (excretion, binding to plasma proteins, metabolical inertia, and the like), and optimal relaxivity properties, that is to say that the values of this parameter should be and remain high, independently of the surrounding environment, in particular the presence of physiological anions and pH changes.